Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.

2

Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.

3

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.

Department of Clinical Neurology, Medical University of Innsbruck, 6020 Austria.

33

Department of Neurology, Medical University of Graz, 8010 Austria.

34

Department of Neurology, Medical University of Vienna, 1090 Austria.

35

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada carles@can.ubc.ca.

Abstract

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

Simplified pedigrees for families presenting the PLG p.G420D variant. Males are represented by squares and females by circles, the proband is indicated with an arrow head. Patients diagnosed with MS have black filled symbols, and carriers of unknown clinical phenotype have gray filled symbols. Heterozygote carriers (M) and wild-type (wt) genotypes are indicated. An asterisk indicates an inferred carrier. Pedigree A was used for exome analysis, and, with the exception of pedigree E, which is of Asian descent, all families are of Caucasian ancestry.